Activated Raf-1 causes growth arrest in human small cell lung cancer cells

Rajani K. Ravi, Erich Weber, Martin McMahon, Jerry R. Williams, Stephen Baylin, Asoke Mal, Marian L. Harter, Larry E. Dillehay, Pier Paolo Claudio, Antonio Giordano, Barry D. Nelkin, Mack Mabry

Research output: Contribution to journalArticle

Abstract

Small cell lung cancer (SCLC) accounts for 25% of all lung cancers, and is almost uniformly fatal. Unlike other lung cancers, ras mutations have not been reported in SCLC, suggesting that activation of ras-associated signal transduction pathways such as the raf-MEK mitogen-activated protein kinases (MAPK) are associated with biological consequences that are unique from other cancers. The biological effects of raf activation in small cell lung cancer cells was determined by transfecting NCI-H209 or NCI-H510 SCLC cells with a germ encoding a fusion protein consisting of an oncogenic form of human Raf- 1 and the hormone binding domain of the estrogen receptor (ΔRaf-1:ER), which can be activated with estradiol. ΔRaf-1:ER activation resulted in phosphorylation of MAPK. Activation of this pathway caused a dramatic loss of soft agar cloning ability, suppression of growth capacity, associated with cell accumulation in G1 and G2, and S phase depletion. Raf activation in these SCLC cells was accompanied by a marked induction of the cyclin- dependent kinase (cdk) inhibitor p27(kip1), and a decrease in cdk2 protein kinase activities. Each of these events can be inhibited by pretreatment with the MEK inhibitor PD098059. These data demonstrate that MAPK activation by ΔRaf-1:ER can activate growth inhibitory pathways leading to cell cycle arrest. These data suggest that raf/MEK/ MAPK pathway activation, rather than inhibition, may be a therapeutic target in SCLC and other neuroendocrine tumors.

Original languageEnglish (US)
Pages (from-to)153-159
Number of pages7
JournalJournal of Clinical Investigation
Volume101
Issue number1
DOIs
StatePublished - Jan 1 1998

Keywords

  • Activated raf
  • Cell cycle
  • MAP kinase
  • MEK inhibitor PD098059
  • SCLC
  • p27(kip1)

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Ravi, R. K., Weber, E., McMahon, M., Williams, J. R., Baylin, S., Mal, A., Harter, M. L., Dillehay, L. E., Claudio, P. P., Giordano, A., Nelkin, B. D., & Mabry, M. (1998). Activated Raf-1 causes growth arrest in human small cell lung cancer cells. Journal of Clinical Investigation, 101(1), 153-159. https://doi.org/10.1172/JCI831